ABSTRACT Cancer metastases to the leptomeninges (LM) are difficult to treat, create significant morbidity, and predict extremely poor survival. There are currently no molecularly targeted approaches to prevent LM disease involvement. LM metastases are frequent in hematologic malignancies such as acute lymphoblastic leukemia (ALL), and the incidence in solid tumors is rising. We recently reported a novel mechanism whereby ALL cells invade the central nervous system (CNS) LM by migrating along the abluminal surface of emissary blood vessels that bridge the vertebral and calvarial bone marrow and subarachnoid spaces. ALL cells hijack a neural stem cell developmental migration pathway involving ?6 integrin receptor and laminin binding interactions in order to crawl along the laminin-rich basement membrane of this unique vasculature. These vessels pass from the bone marrow through apertures in the vertebral or calvarial bone to directly enter the LM. Malignant cells expressing the laminin receptor, ?6, invade along the external surface of this bridging vasculature in an integrin-dependent fashion, bypassing the peripheral circulation and the blood brain barrier to efficiently metastasize to the LM. This finding explains the clinical observation that LM metastases frequently occur in the absence of brain parenchymal disease involvement. In this proposal, we will define the signaling events that are activated in leukemic cells upon ?6 integrin-laminin engagement, determine the role of ?6 integrin-laminin interactions in breast cancer leptomeningeal metastasis, and test the efficacy of downstream PI3K inhibition to target this pathway in mouse models of ALL and breast cancer LM metastasis. These studies will provide new mechanistic insight into a poorly understood biologic phenomenon and a therapeutic approach to an area of high unmet clinical need.